Plasma Autoantibodies Against Neurodegeneration-Related Antigens in Dementia and Elevated Chi3Li Autoantibodies in Mild Cognitive Impairment

Systemic autoimmunity plays an important role in pathogenesis of neurodegenerative diseases. The objective of our study was to explore the seroprevalence of naturally occurring autoantibodies (Aabs) targeting a panel of 14 antigens broadly involved in neurodegenerative diseases such as Alzheimer's Disease, Parkinson's Disease, frontotemporal dementia, and vascular dementia. Commonly associated proteins with underlying neuronal pathology of the brain include amyloid-beta (Aβ), tau, alpha-synuclein (α-syn), TDP-43, and FUS. Proteins associated with glial and astrocytic involvement-TREM2 and Chi3Li; proteins related to myelin damage and axonal degeneration-light neurofilaments (NFL), myelin basic protein (MBP); synaptic loss reflected by neurogranin (NRGN), a marker of neuronal injury-neuron specific enolase (NSE); and markers of disturbed calcium homeostasis-VSNL1 and neuroinflammation-MCP-1. Presence and levels of plasma IgG against these antigens were examined using enzyme-linked immunosorbent assay (ELISA) method in patients with dementia, patients with mild cognitive impairment (MCI), and healthy age-matched controls. Aabs against all selected antigens were detected across all groups, including healthy control, with varied seroprevalence levels. For the first time, we report the presence of anti-FUS, anti-TREM2, anti-NRGN, anti-VSNL1, anti-NSE, and anti-MCP1 Aabs. Elevated anti-Chi3Li Aabs in individuals with MCI indicate a disease-associated immune signature linked to early neurodegenerative processes. Overall, these results provide evidence of systemic immune activation accompanying neurodegeneration, underscore the complexity of immune involvement, and highlight the importance of targeting multiple pathological pathways in future immunomodulatory strategies.